Nanometer and micrometer sized particles are attractive X-ray contrast agents (XCAs) since they contain a large number of X-ray attenuating atoms in a small volume, which should allow use at low concentrations. Additionally the high contrast material will allow for attachment of biomolecules and/or ligands to the particle surface, potentially making highly specific site-directed contrast agents or variably miscible X-ray composite fillers (Cho et al., T. in Molecular Medicine, 2010, 16, 12, 561). Heavy element gold nanoparticles (AuNPs, Z=79) have begun to be explored as nano XCAs, primarily due to the ease of synthesis and morphological control that has been demonstrated for AuNPs over the last several decades (Popovtzer et al., Nano Lett. 2008, 8, 4593; Eck et al., Nano Lett. 2010, 10, 2318). However, gold is very expensive, making AuNPs a somewhat undesirable element for large scale systematic medical use. More importantly, while the oxidative stability of AuNPs infers a synthetic advantage in the laboratory, AuNPs larger than 5 nm pose a biological and environmental toxicity risk since they are not cleared by living organisms and are potentially bio-accumulating (Choi et al., Nat. Biotechnology, 2007, 25(10), 1165; Longmire et al. Nanomedicine, 2008, 3, 5, 703). Other X-ray opaque XCAs and fillers have included iopromide, barium sulfate, tin and lead, each with limitations, and not typically in particle form.
The recent popularity of green chemical techniques has put an emphasis on using water as a synthetic solvent, which can be problematic for metals prone to oxidation. Since any XCA used in a biological organism must have aqueous stability, desirable nanoparticles used as XCAs would be hydrolytically stable and have oxidative protection. The aqueous aerobic stabilization of nanomaterials, particularly those made of electropositive metals and semi-metals, has proven a challenge due to the difficulty in protecting against hydrolytic and oxidative decomposition. Gold has become a model system for the study of nanoparticle formation, stability, and growth mechanisms, in part due to the oxidative inertness of this element. However, most metals are susceptible to the formation of oxides on their surface, which can lead to the eventual oxidative degradation of the material, as in iron, or to protection of the metal, as in aluminum. This makes the stabilization of aqueous metal nanomaterials difficult, as a nanosize particle inherently has a high surface area to volume ratio. The high surface area imparts a variety of unique and desirable properties; however, for non-oxidatively inert elements, the high surface area can pose stability challenges in an aqueous or aerobic environment. In non-polar environments, similar challenges present in stabilizing the high-energy particle surfaces against aggregation.